Food Restriction Reverses the Hyper-Muscular Phenotype and Force Generation Capacity Deficit of the Myostatin Null Mouse

Abstract

Food restriction has a great impact on skeletal muscle mass by inducing muscle protein breakdown to provide substrates for energy production through gluconeogenesis. Genetic models of hyper-muscularity interfere with the normal balance between protein synthesis and breakdown which eventually results in extreme muscle growth. Mutations or deletions in the myostatin gene result in extreme muscle mass. Here we evaluated the impact of food restriction for a period of 5 weeks on skeletal muscle size (i. e., fibre cross-sectional area), fibre type composition and contractile properties (i. e., tetanic and specific force) in myostatin null mice. We found that this hyper-muscular model was more susceptible to catabolic processes than wild type mice. The mechanism of skeletal muscle mass loss was examined and our data shows that the myostatin null mice placed on a low calorie diet maintained the activity of molecules involved in protein synthesis and did not up-regulate the expression of genes pivotal in ubiquitin-mediated protein degradation. However, we did find an increase in the expression of genes associated with autophagy. Surprisingly, the reduction on muscle size was followed by improved tetanic and specific force in the null mice compared to wild type mice. These data provide evidence that food restriction may revert the hyper-muscular phenotype of the myostatin null mouse restoring muscle function.

Key words

myostatin - muscle mass - muscle strength - nutritional intervention

• References

• 1 Amthor H, Macharia R, Navarrete R, Schuelke M, Brown SC, Otto A, Voit T, Muntoni F, Vrbova G, Partridge T, Zammit P, Bunger L, Patel K. Lack of myostatin results in excessive muscle growth but impaired force generation. Proc Natl Acad Sci USA 2007; 104: 1835-1840
• 2 Aspnes LE, Lee CM, Weindruch R, Chung SS, Roecker EB, Aiken JM. Caloric restriction reduces fiber loss and mitochondrial abnormalities in aged rat muscle. FASEB J 1997; 11: 573-581
• 3 Bodine SC, Stitt TN, Gonzalez M, Kline WO, Stover GL, Bauerlein R, Zlotchenko E, Scrimgeour A, Lawrence JC, Glass DJ, Yancopoulos GD. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol 2001; 3: 1014-1019
• 4 Dennemarker J, Lohmuller T, Muller S, Aguilar SV, Tobin DJ, Peters C, Reinheckel T. Impaired turnover of autophagolysosomes in cathepsin L deficiency. Biol Chem 2010; 391: 913-922
• 5 Goldspink G, Ward PS. Changes in rodent muscle fibre types during post-natal growth, undernutrition and exercise. J Physiol 1979; 296: 453-469
• 6 Gondret F, Lebas F, Bonneau M. Restricted feed intake during fattening reduces intramuscular lipid deposition without modifying muscle fiber characteristics in rabbits. J Nutr 2000; 130: 228-233
• 7 Harriss DJ, Atkinson G. Update – ethical standards in sport and exercise science research. Int J Sports Med 2011; 32: 819-821
• 8 Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004; 18: 1926-1945
• 9 Hooper AC. The effect of dietary restriction on muscle fibre length in mice. Br J Nutr 1984; 51: 479-483
• 10 Komatsu M, Ichimura Y. Physiological significance of selective degradation of p62 by autophagy. FEBS Lett 2010; 584: 1374-1378
• 11 Lee CM, Lopez ME, Weindruch R, Aiken JM. Association of age-related mitochondrial abnormalities with skeletal muscle fiber atrophy. Free Radic Biol Med 1998; 25: 964-972
• 12 Li JB, Goldberg AL. Effects of food deprivation on protein synthesis and degradation in rat skeletal muscles. Am J Physiol 1976; 231: 441-448
• 13 Malatesta M, Perdoni F, Battistelli S, Muller S, Zancanaro C. The cell nuclei of skeletal muscle cells are transcriptionally active in hibernating edible dormice. BMC Cell Biol 2009; 10: 19
• 14 Mammucari C, Milan G, Romanello V, Masiero E, Rudolf R, Del Piccolo P, Burden SJ, Di Lisi R, Sandri C, Zhao J, Goldberg AL, Schiaffino S, Sandri M. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab 2007; 6: 458-471
• 15 Masiero E, Agatea L, Mammucari C, Blaauw B, Loro E, Komatsu M, Metzger D, Reggiani C, Schiaffino S, Sandri M. Autophagy is required to maintain muscle mass. Cell Metab 2009; 10: 507-515
• 16 Matsakas A, Bozzo C, Cacciani N, Caliaro F, Reggiani C, Mascarello F, Patruno M. Effect of swimming on myostatin expression in white and red gastrocnemius muscle and in cardiac muscle of rats. Exp Physiol 2006; 91: 983-994
• 17 Matsakas A, Foster K, Otto A, Macharia R, Elashry MI, Feist S, Graham I, Foster H, Yaworsky P, Walsh F, Dickson G, Patel K. Molecular, cellular and physiological investigation of myostatin propeptide-mediated muscle growth in adult mice. Neuromuscul Disord 2009; 19: 489-499
• 18 Matsakas A, Macharia R, Otto A, Elashry MI, Mouisel E, Romanello V, Sartori R, Amthor H, Sandri M, Narkar V, Patel K. Exercise training attenuates the hypermuscular phenotype and restores skeletal muscle function in the myostatin null mouse. Exp Physiol 2012; 97: 125-140
• 19 Matsakas A, Mouisel E, Amthor H, Patel K. Myostatin knockout mice increase oxidative muscle phenotype as an adaptive response to exercise. J Muscle Res Cell Motil 2010; 31: 111-125
• 20 Matsakas A, Patel K. Intracellular signalling pathways regulating the adaptation of skeletal muscle to exercise and nutritional changes. Histol Histopathol 2009; 24: 209-222
• 21 Matsakas A, Patel K. Skeletal muscle fibre plasticity in response to selected environmental and physiological stimuli. Histol Histopathol 2009; 24: 611-629
• 22 Maxwell LC, Enwemeka CS, Fernandes G. Effects of exercise and food restriction on rat skeletal muscles. Tissue Cell 1992; 24: 491-498
• 23 McFarlane C, Plummer E, Thomas M, Hennebry A, Ashby M, Ling N, Smith H, Sharma M, Kambadur R. Myostatin induces cachexia by activating the ubiquitin proteolytic system through an NF-kappaB-independent, FoxO1-dependent mechanism. J Cell Physiol 2006; 209: 501-514
• 24 McKiernan SH, Bua E, McGorray J, Aiken J. Early-onset calorie restriction conserves fiber number in aging rat skeletal muscle. FASEB J 2004; 18: 580-581
• 25 McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 1997; 387: 83-90
• 26 McPherron AC, Lee SJ. Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci USA 1997; 94: 12457-12461
• 27 Mendias CL, Marcin JE, Calerdon DR, Faulkner JA. Contractile properties of EDL and soleus muscles of myostatin-deficient mice. J Appl Physiol 2006; 101: 898-905
• 28 Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 2004; 15: 1101-1111
• 29 Ogata T, Oishi Y, Higuchi M, Muraoka I. Fasting-related autophagic response in slow- and fast-twitch skeletal muscle. Biochem Biophys Res Commun 2010; 394: 136-140
• 30 Otto A, Macharia R, Matsakas A, Valasek P, Mankoo BS, Patel K. A hypoplastic model of skeletal muscle development displaying reduced foetal myoblast cell numbers, increased oxidative myofibres and improved specific tension capacity. Dev Biol 2010; 343: 51-62
• 31 Pursiheimo JP, Rantanen K, Heikkinen PT, Johansen T, Jaakkola PM. Hypoxia-activated autophagy accelerates degradation of SQSTM1/p62. Oncogene 2009; 28: 334-344
• 32 Ruegg MA, Glass DJ. Molecular mechanisms and treatment options for muscle wasting diseases. Annu Rev Pharmacol Toxicol 2011; 51: 373-395
• 33 Sandri M. Autophagy in skeletal muscle. FEBS Lett 2010; 584: 1411-1416
• 34 Sartori R, Milan G, Patron M, Mammucari C, Blaauw B, Abraham R, Sandri M. Smad2 and 3 transcription factors control muscle mass in adulthood. Am J Physiol 2009; 296: C1248-C1257
• 35 Tracy K, Macleod KF. Regulation of mitochondrial integrity, autophagy and cell survival by BNIP3. Autophagy 2007; 3: 616-619
• 36 Trendelenburg AU, Meyer A, Rohner D, Boyle J, Hatakeyama S, Glass DJ. Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size. Am J Physiol 2009; 296: C1258-C1270
• 37 Tsintzas K, Jewell K, Kamran M, Laithwaite D, Boonsong T, Littlewood J, Macdonald I, Bennett A. Differential regulation of metabolic genes in skeletal muscle during starvation and refeeding in humans. J Physiol 2006; 575: 291-303
• 38 Wang L, Rhodes CJ, Lawrence Jr JC. Activation of mammalian target of rapamycin (mTOR) by insulin is associated with stimulation of 4EBP1 binding to dimeric mTOR complex 1. J Biol Chem 2006; 281: 24293-24303
• 39 Zhao J, Brault JJ, Schild A, Cao P, Sandri M, Schiaffino S, Lecker SH, Goldberg AL. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab 2007; 6: 472-483